KRAS modulators and uses thereof
Provided herein are KRAS modulating compounds, such as compounds of Formula (I), (II) (II*) (III) or pharmaceutically acceptable salts, solvates, stereoisomers, atom labelled, or tautomers of any of the foregoing, useful for modulating KRAS GD12 and/or other G12 mutants.
1 . A compound of Formula (II):
or a pharmaceutically acceptable salt thereof wherein:
M is selected from O, NH, and NMe;
n is 0;
R 1 is selected from an unsaturated 5- to 12-membered heterocycle, which is optionally substituted with one or more substituents independently selected from halogen, —B(OR 20 ) 2 , —OR 20 , —SR 20 , —S(O) 2 (R 20 ), —S(O) 2 N(R 20 ) 2 , —NR 20 S(O) 2 R 20 , —C(O)N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —N(R 20 )C(O)N(R 20 ) 2 , —N(R 20 )C(O)OR 20 , —N(R 20 ) 2 , —C(O)R 20 , —C(O)OR 20 , —OC(O)R 20 , —OC(O)N(R 20 ) 2 , —NO 2 , ═O, ═NO(R 20 ), —CN, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
or
R 1 is selected from a 7- to 10-membered heterocycle, which is optionally substituted with one or more substituents independently selected from halogen, —OR 20 , —C(O)N(R 20 ) 2 , —N(R 20 ) 2 , —C(O)R 20 , —S(O) 2 (R 20 ), ═O, C 1-6 cyanoalkyl, and C 1-6 alkyl;
B is selected from a heterocycle and carbocycle, wherein the heterocycle or carbocycle is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, ═O, —NO 2 , C 1 -C 4 alkyl, C 1-6 aminoalkyl, —S—C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 2 -C 4 hydroxyalkynyl, C 1 -C 3 cyanoalkyl, triazolyl, C 1 -C 3 haloalkyl, —O—C 1 -C 3 haloalkyl, —S—C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 hydroxyalkyl, —CH 2 C(═O)N(R 5 ) 2 , —C 3 -C 4 alkynyl-N(R 5 ) 2 , —N(R 5 ) 2 , (C 1 -C 3 alkoxy)haloC 1 -C 3 alkyl-, C 3 -C 12 carbocycle, and 5- to 12-membered heterocycle, wherein the C 3 -C 12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, —OH, —NO 2 , —NH 2 , —O, —S, —CN, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, and C 1-6 haloalkyl;
Y is O;
R 2 is selected from -L-heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R 6 ;
each L is independently selected from a C 1 -C 4 alkylene optionally substituted with one or more substituents selected from hydroxy, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkyl, C 3 -C 6 carbocycle, and 3- to 8-membered heterocycle, wherein the C 3 -C 6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, —OH, —NO 2 , ═O, ═S, —CN, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, and C 1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C 3 -C 6 carbocycle or 3- to 8-membered heterocycle wherein the C 3 -C 6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, —OH, —NO 2 , —O, ═S, —CN, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, and C 1-6 haloalkyl;
each R 6 is independently selected from halogen, hydroxy, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, cyano, C 1 -C 3 aminoalkyl, -Q-phenyl, -Q-phenylSO 2 F, —NHC(O)phenyl, —NHC(O)phenylSO 2 F, C 1 -C 3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH 2 —, —N(R 5 ) 2 , (C 1 -C 3 alkoxy) C 1 -C 3 alkyl-, (C 1 -C 3 alkyl) C(═O)—, oxo, (C 1 -C 3 haloalkyl) C(═O)—, —SO 2 F, (C 1 -C 3 alkoxy) C 1 -C 3 alkoxy, —CH 2 OC(O)N(R 5 ) 2 , —CH 2 NHC(O)OC 1 -C 6 alkyl, —CH 2 NHC(O)N(R 5 ) 2 , —CH 2 NHC(O)C 1 -C 6 alkyl, —CH 2 (pyrazolyl), —CH 2 NHSO 2 C 1 -C 6 alkyl, —CH 2 OC(O)heterocycle, —OC(O)N(R 5 ) 2 , —OC(O)NH(C 1 -C 3 alkyl)O(C 1 -C 3 alkyl), —OC(O)NH(C 1 -C 3 alkyl)O(C 1 -C 3 alkyl)phenyl(C 1 -C 3 alkyl)N(CH 3 ) 2 , —OC(O)NH(C 1 -C 3 alkyl)O(C 1 -C 3 alkyl)phenyl, —OC(O)heterocycle, and —CH 2 heterocycle, wherein the phenyl of —NHC(O)phenyl or —OC(O)NH(C 1 -C 3 alkyl)(C 1 -C 3 alkyl)phenyl is optionally substituted with —C(O) H or —OH and wherein the heterocycle of —CH 2 heterocyclyl is optionally substituted with oxo, wherein Q is O or S;
each R 20 is independently selected from hydrogen; and C 1-6 alkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , —N(C 1-6 alkyl) 2 , C 1-10 alkyl, —C 1-10 haloalkyl, —O—C 1-10 alkyl, oxo, C 3-12 carbocycle, and 3- to 12-membered heterocycle; and
each R 5 is independently selected from hydrogen and C 1 -C 6 alkyl.
2 . The compound or salt of claim 1 , wherein Mis O.
3 . The compound or salt of claim 1 , wherein Mis NMe.
4 . The compound or salt of claim 1 , wherein R 1 is selected from a 7- to 10-membered heterocycle, which is optionally substituted with one or more substituents independently selected from halogen, —OR 20 , —C(O)N(R 20 ) 2 , —N(R 20 ) 2 , —C(O)R 20 , —S(O) 2 (R 20 ), ═O, C 1-6 cyanoalkyl, and C 1-6 alkyl.
5 . The compound or salt of claim 1 , wherein R 1 is selected from an unsaturated 5- to 12-membered heterocycle, which is optionally substituted with one or more substituents independently selected from halogen, —B(OR 20 ) 2 , —OR 20 , —SR 20 , —S(O) 2 (R 20 ), —S(O) 2 N(R 20 ) 2 , —NR 20 S(O) 2 R 20 , —C(O)N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —N(R 20 )C(O)N(R 20 ) 2 , —N(R 20 )C(O)OR 20 , —N(R 20 ) 2 , —C(O)R 20 , —C(O)OR 20 , —OC(O)R 20 , —OC(O)N(R 20 ) 2 , —NO 2 , ═O, ═NO(R 20 ), —CN, C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl.
6 . The compound or salt of claim 5 , wherein R 1 is selected from
which is optionally substituted.
7 . The compound or salt of claim 6 , wherein R 1 is selected from
which is optionally substituted with one or more substituents independently selected from halogen, —C(O)N(R 20 ) 2 , —N(R 20 ) 2 , —C(O)R 20 , —C(O)OR 20 , —CN, C 1-6 cyanoalkyl, C 1-6 alkyl, and C 2-6 alkynyl.
8 . The compound or salt of claim 7 , wherein R 1 is
9 . The compound or salt of claim 7 , wherein R 1 is
10 . The compound or salt of claim 1 , wherein B is selected from
each of which is optionally substituted with one or more substituents.
11 . The compound or salt of claim 10 , wherein B is selected from
each of which is optionally substituted with one or more substituents.
12 . The compound or salt of claim 11 , wherein the one or more optional substituents are independently selected from oxo, —NH 2 , —CN, halogen, and C 1 -C 3 alkyl.
13 . The compound or salt of claim 11 , wherein B is selected from
14 . The compound or salt of claim 1 , wherein L is selected from C 1 -C 4 alkylene.
15 . The compound or salt of claim 14 , wherein L is selected from unsubstituted C 1 -C 4 alkylene.
16 . The compound or salt of claim 15 , wherein Y—R 2 is selected from
wherein the heterocycle portion is optionally substituted with one or more R 6 .
17 . The compound or salt of claim 16 , wherein R 6 of R 2 is independently selected at each occurrence from C 1 -C 3 alkyl and halogen.
18 . The compound or salt of claim 1 , wherein Y—R 2 is selected from
19 . The compound or salt of claim 1 , wherein Y—R 2 is
20 . The compound or salt of claim 1 , wherein Y—R 2 is
21 . The compound or salt of claim 1 , wherein Mis O; R 1 is selected from
which is optionally substituted with one or more substituents independently selected from halogen and —C(O)N(R 20 ) 2 ; B is selected from
which is optionally substituted with one or more substituents selected from —NH 2 , —CN, and C 1 -C 3 alkyl; and Y—R 2 is
22 . The compound or salt of claim 1 , wherein Mis NMe; R 1 is selected from
which is optionally substituted with one or more substituents independently selected from halogen and —C(O)N(R 20 ) 2 ; B is selected from
which is optionally substituted with one or more substituents selected from —NH 2 , —CN, and C 1 -C 3 alkyl; and Y—R 2 is
23 . The compound or salt of claim 1 , wherein the compound is selected from
or a salt of any one thereof.
24 . The compound or salt of claim 1 , wherein the compound is selected from
or a salt of any one thereof.
25 . The compound or salt of claim 1 , the compound is selected from
or a salt of any one thereof.
26 . A pharmaceutical composition comprising a compound or salt of claim 1 and a pharmaceutically acceptable excipient.
27 . A method of treating a disease or disorder, comprising administering to a patient in need thereof the pharmaceutical composition of claim 26 , wherein the disease or disorder is a cancer selected from:
Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma;
Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;
Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);
Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma);
Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;
Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma;
Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors;
Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);
Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma);
Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);
Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and
Adrenal glands: neuroblastoma.
28 . The compound or salt of claim 1 , wherein R 1 is selected from an optionally substituted 7- to 10-membered fused heterocycle.